Stress proteins are a very highly conserved group of proteins (Schlesinger, M. J. (1994) "How the Cell Copes with Stress and the Function of Heat Shock Proteins," Pediatric Research, 36(1 Pt 1): 1-6). This term, stress protein, includes both heat shock proteins and glucose regulated proteins and other candidate proteins, such as Erp72. Certain members of the stress proteins are constitutively expressed and are essential components of the cellular machinery. Other members of the group are not readily detectable under normal circumstances but in situations of stress and injury, such as ischemia, (Perdrizet, G. A., Kaneko, H., et al. (1993) "Heat shock and recovery protects renal allografts from warm ischemic injury and enhances hsp72 production," Transplantation proceedings 25(1 Pt 2): 1670-3), hyperthermia. (Chatson, G., Perdrizet, G., et al. (1990) "Heat shock protects kidneys against warm ischemic injury," Current Surgery 47(6): 420-3), physical trauma, reperfusion injury, the expression of these proteins are greatly upregulated (Currie, R. W., White, F. P. (1981) "Trauma-induced protein in rat tissues: a physiological role for a `heat shock` protein?" Science 214(4516): 72-3). Some of these proteins are also specifically upregulated by treatment of cells of almost any origin, with various chemical and physical agents, such as arsenite, radiation, UV light exposure, chemical compounds including Calcium Ionophore A23187 (Resendez, Jr., E., Attenello, J. W., et al. (1985) "Calcium ionophore A23187 induces expression of glucose-regulated genes and their heterologous fusion genes" Molecular & Cellular Biology 5(6): 1212-9). The existence of the heat shock response which causes the expression of these stress proteins was initially described in 1962 with the observation that Drosophila salivary gland chromosomes puffed when exposed to supraphysiological temperatures (Ritossa, F. M. (1962) "A new puffing pattern induced by a temperature shock and DNP in Drosophilal" Experientia 18: 571-573). When the existence of the stress proteins were discovered it became apparent that by inducing the expression of these proteins in a cell it may lead to increased resistance of the cell to similar stresses (Tissieres, A., Mitchell, H. K., et al. (1974) "Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs" Journal of Molecular Biology 84(3): 389-98). The stress proteins as a group are however also intricately involved in the process of antigen presentation by cells of all types in the human and animal organism or body (Williams, DB, W. T. (1995) "Molecular chaperones in antigen presentation" Current Opinion in Immunology 1(7): 77-84; Li, Z. and Srivastava, P. K. (1994) "A critical contemplation on the role of heat shock proteins in transfer of antigenic peptides during antigen presentation" Behring Institute Mitteilungen (94): 37-47; Udono, H. and Srivastava, P. K. (1993) "Heat shock protein 70-associated peptides elicit specific cancer immunity" Journal of Experimental Medicine 178(4): 1391-6; Mariethos, E., Tacchini-Cottier, F., et al. (1994) "Exposure of monocytes to heat shock does not increase class II expression but modulates antigen-dependent T cell responses" International Immunology 6(6): 925-930; Hightower, L. E., Sadis, S. E., et al. (1994) "Interactions of vertebrate hsc70 and hsp70 with unfolded proteins and peptides" The Biology of Heat Shock Proteins and Molecular Chaperones. R. L. Morimoto, A. Tissieres and C. Georgopoulos. Plainview, N.Y., Cold Spring Harbor Laboratory Press: 179-208; Buskirk, A. V., Crump, B. L., et al. (1989) "A peptide-binding protein having a role in antigen presentation is a member of the HSP70 heat shock protein family" J. Exp. Med. 179: 1799; and Ryan, C., Stevens, T. H., et al. (1992) "Inhibitory effects of hsp70 chaperones on nascent polypeptides" Protein Science 1(8): 980-5). Evidence has been presented to support the possibility that these proteins may also be secreted or released in the immediate environment of the stressed cell or tissue (Hightower, L. E., Guidon, Jr., P. T., (1989) "Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins" Journal of Cellular Physiology 138(2): 257-66). Experimental data has also shown that there is reason to believe that secreted or released stress proteins can once again be ingested by a number of other specialized cells including macrophages (Suto, R. and Srivastava, P. K. (1995) "A Mechanism for the Specific Immunogenicity of Heat Shock Protein-Chaperoned Peptides" Science 269 (Sep. 15, 1995): 1585-1588) and dendritic cells (own data).
The allo-immune response is dependent on the recognition by host cytotoxic lymphocytes of allo-MHC (Major Histo Compatibility) molecule and donor peptide complexes. This recognition has to lead to an effector response to cause rejection of an allograft or xenograft, although other mechanisms may also be important in xenotransplant rejection. This recognition and response is dependent on activation of donor MHC complex specific host T-lymphocytes by donor derived antigen presentation cells (including macrophages and dentritic cells and possibly other cell types) or specific subsets of donor antigen presenting cells (Thomas, R., Davis, L. S., et al. (1993) "Comparative accessory cell function of human peripheral blood dendritic cells and monocytes" Journal of Immunology 151(12): 6840-52). It has long been known that by appropriate pre-treatment of a recipient animal or human with a variety of treatment protocols, long lasting tolerance (non-rejection) of the allo- and xenograft can be induced (Zimmerman, C. E., Stuart, F. P., et al. (1965) "Dog renal homografts prolonged by antigenic pretreatment" Surgical Forum 16: 267-9; and Sykes, M., Lee, L. A., et al. (1994) "Xenograft tolerance" Immunological Reviews 141: 245-76). The mechanism by which the tolerance is induced is as yet unclear. The induction of donor specific tolerance to an allo- or xenograft is the ultimate goal of transplantation immune modulation. Although the effects and role of stress proteins in biological systems has been widely investigated in context of auto-immune disease (Lamb, J. R., Bal, V., et al. (1989) "Stress proteins may provide a link between the immune response to infection and autoimmunity" Int. Immunol. 1: 191-196) and cancer immunity (Srivastava, P. K., Heike, M. (1991) "Tumor-specific immunogenicity of stress-induced proteins: convergence of two evolutionary pathways of antigen presentation?" Seminars in Immunology 3(1): 57-64) it has not been the case for the possible involvement of stress proteins in the biology of transplant immunology. The majority of published works on the role of stress proteins in transplant immunology has focused on the demonstration of stress protein expression by grafted organs (Currie, R. W. (1987) "Effects of ischemia and perfusion temperature on the synthesis of stress-induced (heat shock) proteins in isolated and perfused rat hearts" Journal of Molecular & Cellular Cardiology 19(8): 795-808; Qian, J., Moliterno, R., et al. (1995) "Expression of heat shock proteins and lymphocyte reactivity in rat cardiac allografts undergoing cellular rejection" Transplant Immunology: In Press; and Davis, E. A., Wang, B. H., et al. (1995) "Induction of Heat Shock Protein in a Model of Acute Cardiac Allograft Rejection" Personal Communication). No such investigation of xenografts has been undertaken. The remaining published works focus on the demonstration of T-cell lymphocytes with specific reactivity against stress proteins and specifically heat shock proteins (Mycobacterial tuberculosis hsp71) and glucose regulated proteins (murine grp78) both of which are recombinant proteins expressed in an E. coli expression system. (Moliterno, R., Valdivia, L., et al. (1995) "Heat shock protein reactivity of lymphocytes isolated from heterotopic rat cardiac allografts" Transplantation: In Press; and Moliterno, R., Woan, M., et al. (1995) "Heat shock protein-induced T lymphocyte propagation from endomyocardial biopsies in heart transplantation" Journal of Heart and Lung Transplantation: In Press). On reinterpretation of these data it becomes clear that the reactivity of these T-lymphocytes propagated from allografts are in fact not directed to hsp or grp but to an unknown E. coli peptide contained in the stress protein. This is in concordance with the published function of the stress proteins in antigen presentation (DeNagel, D. C., and Pierce, S. K., (1993) "Heat shock proteins in immune responses" Critical Reviews in Immunology 13(1): 71-81; Lakey, E. K., Margoliash, E., et al. (1987) "Identification of a peptide binding protein that plays a role in antigen presentation" Proc. Natl. Acad. Sci. USA 84: 1659-1663; and Pierce, S. K. (1994) "Molecular chaperones in the processing and presentation of antigen to helper T cells" Experientia 50: 1026-1030).